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How to explore a patient with a chronic axonal polyneuropathy
Handbook of Clinical Neurology, Vol. 115 (3rd series) Peripheral Nerve Disorders G. Said and C. Krarup, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 14
How to explore a patient with a chronic axonal polyneuropathy AMPARO GUTIERREZ AND JOHN D. ENGLAND* Department of Neurology, Louisiana State University Health Science Center, New Orleans, LA, USA
INTRODUCTION Peripheral neuropathies are common in neurological practice, and there are a variety of clinical presentations. The prevalence in the general population may be as high as 2.4% (Hughes, 2002). Through a combination of clinical findings, electrodiagnostic testing, and laboratory investigations tailored to the individual patients’ circumstances, most neuropathies can be categorized into their different subtypes, sensory being the most common followed by mixed types of neuropathy (both sensory and motor) and rarely pure motor. We will explore in this chapter how to evaluate a patient presenting with a chronic axonal polyneuropathy, which is one of the most common varieties of polyneuropathy seen.
EPIDEMIOLOGY The overall prevalence of polyneuropathy is about 2400 (2.4%) per 100 000, but it is much more prevalent in individuals older then 55 years of age, rising to 8000 (8%) per 100 000 (Martyn and Hughes, 1997). In the developed world the most common cause of peripheral neuropathy is diabetes mellitus. A community-based study estimated the prevalence of peripheral neuropathy in patients with type 2 diabetes mellitus to be 26.4% (Davies et al., 2006). In other parts of the world, such as Southeast Asia, India, and Africa, leprosy is still a major contributing cause of peripheral polyneuropathy.
DIAGNOSIS Although the clinical manifestations of a chronic neuropathy may vary widely, most can be categorized into a relatively limited number of possibilities on the basis of a
thorough history, focused neurological examination, and electrodiagnostic studies. The approach to the evaluation of the patient with a chronic axonal polyneuropathy should occur in a logical, evidence-based, and sequential manner. Historical features are indispensable for an accurate diagnosis. The physician should explore the presence of other medical conditions (including dietary supplements and vitamins), or exposure to toxins such as alcohol, heavy metals, and organic solvents. It is important to determine the rate of symptom progression, type of fibers involved, and pattern of symptoms. The most common clinical phenotype is that of slowly evolving distal sensory loss with varying degrees of muscle weakness, and occasionally autonomic symptoms. Symptoms are usually present for greater then 2 months and slowly worsen over time. The most common variety of polyneuropathy is a chronic distal symmetrical polyneuropathy (Rosenberg and Vermeulen, 2004). In this type of neuropathy nerves are involved in a “length- dependent” fashion; as such, symptoms usually begin in the toes/distal feet and spread centripetally. Sensory symptoms usually precede motor weakness. Myotatic reflexes are also affected in a length-dependent manner such that ankle reflexes are depressed or absent prior to the loss of other reflexes. The clinical picture is usually one of a stocking-glove sensory loss, distal wasting and weakness, and depressed or absent myotatic reflexes. This is an easily recognizable entity. Another form of neuropathy that is frequently encountered is a painful small fiber neuropathy. These patients commonly complain of burning pain, lancinating pain, burning dyesthesias, and sheet intolerance, but at the same time have a feeling of numbness. At onset the symptoms are infrequent or migratory in nature, and as time goes by the symptoms may become more persistent.
*Correspondence to: John D. England, M.D., The Grace Benson Professor and Head, Department of Neurology, LSUHSC School of Medicine, 1542 Tulane Avenue, Rm 721, New Orleans, LA 70112, USA. Tel: 504-568-4082, Fax: 504-568-7130, E-mail: jengla@ lsuhsc.edu
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The symptoms follow a distal to proximal distribution in most patients. On examination one mainly finds distal loss of pin prick, and temperature sensibility. These patients often present with complaints of chronic pain and the diffuse pain may be so severely disabling that it may limit a patient’s overall ability to function. Electrodiagnostic studies are sensitive, specific, and validated measures that are very useful in the assessment of peripheral neuropathy (Dyck et al., 1987). Utilizing electrodiagnostic studies one can determine whether the neuropathy is consistent with axonal loss or demyelination. Nerve conduction studies assess the shape, amplitude, latency, and velocity of most commonly affected nerves. Axonal loss leads to lower amplitudes and relatively preserved latencies and velocities. EMG can be useful in detecting active axonal damage, as evidenced by the presence of spontaneous muscle fiber activity at rest, as well as identifying signs of reinnervation damage in muscle. Electrodiagnostic studies are frequently normal in a painful neuropathy, where the small fibers are the ones mainly affected. In this type of neuropathy intraepidermal skin biopsy, as well as autonomic testing may serve as the most useful tools (England et al., 2009a).
ROLE OF LABORATORY TESTING Laboratory testing should start at potentially identifying the most common causes of axonal neuropathies and escalate in a determined fashion pending the obtained results. The majority of studies indicate that screening laboratory tests should initially consist of a complete blood count, erythrocyte sedimentation rate, a comprehensive metabolic panel (blood glucose, renal function, liver function), thyroid tests, serum B12, and serum protein electrophoresis. The above laboratory studies were identified as useful in current evidence-based practice guidelines (England et al., 2009b). The screening blood test with the highest yield is the blood glucose test, consistent with the well-known fact that diabetes mellitus is the most common cause of a distal symmetrical polyneuropathy. Several studies have highlighted the relatively high prevalence of prediabetes (impaired glucose tolerance) in patients who do not fulfill the criteria for definite diabetes mellitus (Novella et al., 2001). In these patients a glucose tolerance test, fasting blood glucose, or glycosylated hemoglobin should be considered as screening test for prediabetes. This test is particularly useful in screening patients with a small fiber painful neuropathy of unknown etiology. Vitamin B12 deficiency is frequently seen in patients with polyneuropathy. The yield of uncovering this deficiency is even greater when the metabolites of cobalamin (methylmalonic acid and homocysteine) are tested
(Saperstein et al., 2003). A large study demonstrated that measuring methylmalonic acid is more specific then homocysteine (Savage et al., 1994). Methylmalonic acid with or without homocysteine should also be checked when B12 is at the lower range of normal. Recent attention has been drawn to the complication of metformin use and B12 malabsorption, which occurs in 30% of diabetic subjects taking this medication (Tomkin, 1973). Monoclonal gammopathies are more common in patients with polyneuropathy than in the normal population. IgM monoclonal gammopathies may be associated with autoantibody activity, type I or II cryoglobulinemia, macroglobulinemia, or chronic lymphocytic leukemia. IgG or IgA monoclonal gammopathies may be associated with myeloma, POEMS syndrome, primary amyloidosis (Fig. 14.1), or chronic inflammatory conditions. One study of 279 consecutive patients with a polyneuropathy of unknown etiology found that 10% of these patients had a monoclonal gammopathy, a significant increase over that reported in community studies (Kelly et al., 1981). Serum protein immunofixation electrophoresis is more sensitive than serum protein electrophoresis, especially for detecting small or nonmalignant monoclonal gammopathies (Kahn and Bina, 1988). The yield of serum protein immunofixation electrophoresis is increased by 10% over routine SPEP for finding a monoclonal gammopathy. Therefore immunofixation is recommended. The history, clinical picture, and features of the electrodiagnostic studies found in the individual patient will determine if additional laboratory testing is necessary. An important aspect of the history in patients with a
Fig. 14.1. Sporadic familial amyloid polyneuropathy. Endoneurial deposit of amyloid in a sural nerve biopsy from a patient with a late onset, sporadic presentation of transthyretin-familial amyloid polyneuropathy. Note the predominant involvement of small myelinated fibers. 63. (From Plante-Bordeneuve et al. (2007). Diagnostic pitfalls in sporadic transthyretin-familial amyloid polyneuropathy (TTR-FAP). Neurology 69: 693–698.)
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY chronic axonal polyneuropathy is inquiry into the presence of other medical conditions, symptoms of systemic disease, recent viral or other infectious diseases, recent vaccinations, medications (including dietary supplements and vitamins), or exposure to toxins such as alcohol, heavy metals, or organic solvents (Tables 14.1 and 14.2). Laboratory testing should then be done to identify any underlying condition or possible etiology. If there is a suspicion of infection, inflammatory disease, or neoplasm, the cerebrospinal fluid should be analyzed as well. If, chronic heavy metal intoxication is suspected, analysis of the hair or nails should be done (England and Asbury, 2004).
ROLE OF GENETIC TESTING Hereditary neuropathies are an important subtype of polyneuropathy with a prevalence of 1:2500 people. They constitute a hereditary motor and sensory neuropathy and are the most common inherited disorder of the peripheral nervous system (Lupski and Garcia, 2001). A comprehensive family history should always be obtained in patients with a polyneuropathy. It is important to keep in mind that the hereditary neuropathies may exhibit phenotypic variability within families and that spontaneous genetic mutations do occur. The majority of genetically determined polyneuropathies are variants of Charcot Marie Tooth (CMT) disease. The two common causes of a hereditary demyelinating polyneuropathy are CMT1A, where patients exhibit a duplication of the PMP22 gene and CMTX (Wise et al., 1993). Axonal forms of CMT, Type 2, are most commonly caused by MFN2 mutations, these account for 20 21% of Type 2 cases (Saporta et al., 2011). An X-linked form of CMT, CMTX, is caused by mutations in connexin 32. Interestingly, this mutation may manifest as either an axonal or demyelinating neuropathy (Bort et al., 1997). CMTX is the most common type of “axonal” hereditary neuropathy. The high cost of genetic testing necessitates a logical stepwise approach to testing (Fig. 14.2).
ROLE OF CLINICAL AUTONOMIC TESTING Autonomic nervous system dysfunction may be part of a chronic axonal polyneuropathy. In distal axonal symmetrical polyneuropathies with autonomic involvement, the most common clinical findings are abnormalities of sweating and circulatory instability in the feet (England et al., 2009e). Various types of autonomic testing exist and provide indices of cardiovagal, adrenergic, and postganglionic sudomotor function. Heart rate variability is a simple and reliable test of cardiovagal function. It can detect
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the presence of diabetic polyneuropathy with nearly the same sensitivity as nerve conduction studies (Dyck et al., 1992). The quantitative sudomotor axon reflex test (QSART) may be used and can detect distal sudomotor loss with a sensitivity of 75 90% (England et al., 2009c). Analysis of available studies on autonomic testing indicate that a combination of autonomic reflex screening tests provide distinct advantages over just using a single modality (Stewart et al., 1992). The composite autonomic scoring scale (CASS), which includes QSART, orthostatic blood pressure, heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat BP measurement to Phases II and IV of the Valsalva manuver, tilt and deep breathing provides the highest sensitivity and specificity for documentation of autonomic dysfunction (England et al., 2009d).
ROLE OF NERVE BIOPSY There is little indication for a nerve biopsy in the usual cases of chronic distal symmetrical axonal polyneuropathy. Nerve biopsy should be considered when the diagnosis remains uncertain after laboratory and electrodiagnostic testing have been done, or when confirmation of the diagnosis is needed before initiating aggressive therapies. Nerve biopsy can be extremely valuable in cases of suspected vasculitic (Fig. 14.3), inflammatory, infectious, or neoplastic diseases, which can rarely present as a symmetrical polyneuropathy (Said, 2001).
ROLE OF SKIN BIOPSY Epidermal skin biopsy can be performed in patients with burning, numbness, and pain in whom the nerve conductions are usually normal. These patients may have involvement of the small, somatic, unmyelinated intraepidermal nerve fibers which can be quantified by the skin biopsy. The skin biopsy can also assess the autonomic fibers innervating sweat glands (Sommer and Lauria, 2007). Skin biopsy is a technique that involves a 3 mm punch biopsy of skin taken from standardized sites on the leg. The tissue is immunostained with antiprotein-gene-product (PGP) 9.5 antibodies. Both bright-field immunohistochemistry and indirect immunofluorescence have provided standard values of intraepidermal nerve fiber density (Chien et al., 2001). Staining with PGP 9.5 allows for identification and counting of intraepidermal nerve fibers (IENF). This technique has been validated as a reliable method for IENF density determination with good intra- and interobserver reliability in normal controls and patients with a distal symmetrical polyneuropathy (Goranson et al., 2004). In particular, patients who are suspected of having a predominately small fiber length-dependent
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Table 14.1 Different etiologies of axonal polyneuropathies Diseases: Diabetes mellitus Renal insufficiency Liver disease Porphyria Malabsorption (inflammatory bowel and short bowel) Celiac disease Primary systemic amyloidosis Leprosy Lyme HIV infection Carcinoma Lymphoma IgG, IgA Cryglobulinemia Multiple myeloma Drugs: Amiodarone Chloramphenicol Chloroquine Colchicine Dichloroacetate Disulfiram Hydralazine Interferon-a Isoniazid Leflunomide Metronidazole Misonidazole Nitrofurantoin Nucleosides (antiretrovirals) Phenytoin Taxol Thalidomide Vinca alkaloids Toxins: Acrylamide monomer Arsenic Alcohol Carbon disulfide Ethylene oxide Hexacarbons Methyl bromide Mercury Organophosphates Thallium
Symptoms S, SM rarely M SM S or SM M or SM S or SM
Comments Most common Controlled with dialysis Mild Rare Deficiency of vitamins E or B12, some basis unknown
S or SM SM, may have small fiber component S, SM S>M S>M SM SM SM SM S, M, or SM
May have autoimmune basis Most have serum paraprotein, small fiber with autonomic symptoms Involves cutaneous nerves in cold parts of the body Focal or multifocal radiculopathy or neuropathy, facial neuropathy common Mainly lung cancer, positive antibodies (Anti-Hu, Anti-CV2 and Anti-Ri)
Chronic hepatitis C Uncommon
SM SM SM S or SM SM SM S>M S, SM SM S, SM S or SM S or SM SM S>M S>M S>M S>M S>M
Dose related Rare Principle toxicity is myopathy Principle toxicity is myopathy Delayed onset After months to years of exposure Pyridoxine antagonist Reversible, uncommon Pyridoxine antagonist Panmodal Mainly large fiber Dose-related toxicity Rapidly progressive Painful, limits dose exposure Doses > 200 mg/day Doses > 200 mg/m2 Insensitivity to pain and touch Onset in hands > feet, autonomic neuropathy
S>M
Large fiber neuropathy, can mimic Guillain Barre Syndrome (GBS); cause encephalopathy with large doses Painful sensory symptoms, prominent systemic effects Panmodal sensory loss Sensory symptoms followed by motor Inhalational exposure Inhalational abuse Loss of color vision early Predominately motor, usually with tremor Delayed neuropathy after exposure, myelopathy can be seen Painful sensory neuropathy, alopecia, systemic effects
SM S, SM S>M SM SM M>S M>S M>S S>M
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY
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Table 14.2 Purely sensory types Diseases: Vitamin B12 Acromegaly Chronic obstructive pulmonary disease Carcinoma
S S S S
Connective tissue disease: systemic lupus, rheumatoid arthritis, systemic sclerosis, Sjogren’s Drugs: Almitrine Bortezomib Ethambutol Etoposide(VP-16) Nitrous oxide
May be associated with myelopathy Carpal tunnel frequent Only in severe cases Paraneoplastic ganglionitis with small cell or breast cancer, positive antibodies (Anti-Hu, Yo, Ri, Tr, MA, and CV2) Systemic manifestations
S
S S S S S
Platinum drugs: cisplatin carboplatin oxaliplatin
S
Pyridoxine
S
Panmodal sensory loss, reversible Painful, most recover after drug is stopped Mild, reversible Not frequent Inhalational abuse, presents with ataxia, megaloblastic anemia (worsen in presence of B12 deficiency) Severe large fiber, dose related Distal large fiber, associated with hypomagnesemia Less common but also distal large fiber Acute neurosensory syndrome with dysesthesias and cold-induced pharyngolaryngeal dysesthesias, and late cumulative distal large fiber (>540 mg/m2) Doses > 200 mg/day
S-sensory, M-motor
Evaluation of suspected hereditary neuropathies Positive Family History
Negative Family History
EMG/NCS
EMG/NCS
Demyelinating
Index of suspicion for CMT high
Axonal 30% of mutations are de novo, molecular testing
AR
AD
GJB1 12%
MFN2 mut 21%
AR
Second tier
PMP22 dup 70%
X
MPZ mut 5% PMP22 mut 2.5%
MPZ mut 5%
Third tier
First tier
AD
EGR2 mut LITAF mut
RAB7 mut GDAP1 mut GARS mut NEFL mut HSPB1 mut
PRX mut GDAP1 mut
X GJB1 12%
Demyelinating
Axonal
PMP22 dup GJB1 mut
MFN2 mut GJB1 mut
MPZ mut 5% PMP22 mut 2.5%
MPZ mut 5%
EGR2 mut LITAF mut PRX mut GDAP1 mut
RAB7 mut GARS mut NEFL mut HSPB1 mut GDAP1 mut
Fig. 14.2. Decision algorithm for use in the diagnosis of suspected hereditary polyneuropathies using family history and NCSs. PMP22, peripheral myelin protein 22; MPZ, myelin protein zero; PRX, periaxin; GDAP1, ganglioside-induced differentiationassociated protein 1; GJB1, gap-junction beta-1 protein (connexin 32); MFN2, mitofusin 2; EGR2, early growth response 2; LITAF, lipopolysaccharide-induced tumor necrosis factor a; RAB7, small guanosine triphosphate late endosomal protein; GARS, glycyl-transfer RNA synthetase; NEFL, neurofilament light chain; HSPB1, heat shock protein beta-1. (Reprinted and modified with permission from England et al., 2009c.)
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Fig. 14.3. Necrotizing arteritis in a muscle biopsy specimen. Paraffin embedded section of a muscle biopsy specimen from a patient with mononeuritis multiplex, to show fibrinoid necrosis and transmural cellular infiltration. H & E. Original magnification: 25.
sensory polyneuropathy may benefit from skin biopsy with IENF analysis since this test will demonstrate the reduction in the density of intraepidermal nerve fibers typically found in the distal rather than proximal leg, thereby helping to confirm the diagnosis (Fig. 14.4).
ETIOLOGIES OF CHRONIC POLYNEUROPATHIES Painful small fiber neuropathies
Fig. 14.4. (A) Normal epidermal fiber density. (B) Abnormal epidermal fiber density. (By permission of Therapath.)
Painful small fiber neuropathies are more likely associated with diabetes, prediabetes, sporadic amyloidosis, HIV infection, and alcohol abuse. Tangier and Fabry diseases, two inherited disorders, may also rarely present with a small fiber painful neuropathy. Hyperlipidemia has recently been recognized as a potential risk factor for a small fiber neuropathy (Hughes et al., 2004). Neuropathic pain is frequently reported in patients with sarcoidosis, a multisystemic inflammatory disorder characterized by the presence of granulomas (Fig. 14.5). One study reported that 30% of patients with sarcoid complained of burning feet and one third of them had a small fiber neuropathy (Bakkers et al., 2009). Many cases of painful “small fiber” neuropathy remain crytogenic even after a thorough workup.
Chronic sensory or sensory motor neuropathies This form of neuropathy constitutes the largest diagnostic group. There are many etiologies of this neuropathy including systemic causes, metabolic abnormalities, nutritional deficiencies, and exogenous toxins (Tables 14.1 and
Fig. 14.5. Epineural sarcoid granuloma–superficial peroneal nerve biopsy specimen from a patient with multifocal neuropathy. The neighboring nerve fascicles look normal at this level. 1 mm thick plastic section. Thionin blue. Original magnification: 40.
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY 14.2). The most prevalent etiology in the developed world is diabetes and prediabetes (Dyck and Thomas, 1999; Novella et al., 2001; Sumner et al., 2003). Less frequently a chronic axonal polyneuropathy may be immune mediated. The associated monoclonal proteins are mostly IgM or IgG; in some cases there is binding to sulfatide. Even less frequently there may be a polyneuropathy associated with IgA monoclonal gammopathy. Clinically overt peripheral nervous system (PNS) involvement is common in patients with cancer, occurring in 1.7 16% of cases (Croft and Wilkinson, 1965). Chemotherapy and radiotherapy are the most common causes of PNS disorders in patients with cancer. The combination of several neurotoxic products, especially in the case of cancer recurrence, or the association of neurotoxic chemotherapy and radiotherapy, increases the risk of toxic side-effects, which explains some severe neuropathies (Antoine and Camdessanche, 2007) (Fig. 14.6). Malignancies are sometimes associated with production of specific autoantibodies which may be associated with chronic axonal neuropathies. Neuropathies associated with anti-Hu antibodies (also known as ANNA-1) are the most frequent and consist mainly of a subacute sensory neuronopathy (Lucchinetti et al., 1998). Less frequent are neuropathies associated with anti-CV2 (anti-CRMP5) which are usually sensorimotor axonal neuropathies. The most frequently associated cancer is small cell carcinoma (Amato and Collins, 1998). Malignant, in particular leukemic and lymphamatous, cells can occasionally infiltrate peripheral nerves leading to a polyneuropathy (Kelly and Karcher,
Fig. 14.6. Malignant infiltrate in peripheral nerves. Malignant infiltration in a superficial radial nerve biopsy specimen from a patient with a subacute progressive multifocal polyneuropathy and monoclonal gammopathy. Note the presence of malignant cells in the subperineurial and in the epineurial areas. 1 mm thick plastic section. Thionine blue. Original magnification: 63.
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2005). Rarely, a peripheral neuropathy can be seen in non-Hodgkin lymphomas and Hodgkin disease (Briani et al., 2011).
CONCLUSION The cause of most polyneuropathies is evident when the information obtained from the medical history, neurological examination, and electrodiagnostic studies are combined with simple screening laboratory tests. A comprehensive investigation yields an etiological diagnosis in a substantial number of neuropathies, although in 10 15% of patients with a chronic polyneuropathy a cause cannot be found; this idiopathic neuropathy presents more often in middle or old age (McLeod et al., 1984).
REFERENCES Amato AA, Collins MP (1998). Neuropathies associated with malignancy. Semin Neurol 18: 125–144. Antoine JC, Camdessanche JP (2007). Peripheral nervous system involvement in patients with cancer. Lancet Neurol 6: 75–86. Bakkers M, Merkies ISJ, Lauria G et al. (2009). Intraepidermal nerve fiber density and it’s application in sarcoidosis. Neurology 73: 1142–1148. Bort S, Nelis E, Timmerman V et al. (1997). Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot Marie Tooth disease and hereditary neuropathy with liability to pressure palsies. Hum Genet 99: 746–754. Briani C, Vitaliani R, Grisold W et al. (2011). Spectrum of paraneoplastic disease associated with lymphoma. Neurology 76: 705–710. Chien HF, Tseng TJ, Lin WM et al. (2001). Quantitative pathology of cutaneous nerve terminal degeneration in the human skin. Acta Neuropathol 102: 455–461. Croft PB, Wilkinson M (1965). The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. Brain 88: 427–434. Davies M, Brophy S, Williams R et al. (2006). The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 29: 1518–1522 [abstract]. Dyck PJ, Thomas PK (1999). In: Saunders (Ed.), Diabetic Neuropathy. 2nd edn. W.B Saunders, Philadelphia, pp. 255–278. Wiley & Sons, Ltd. chapter 25. Dyck PJ, Bushek W, Spring EM et al. (1987). Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy. Diabetes Care 10: 432–440. Dyck PJ, Karnes JL, O’Brien PC et al. (1992). The Rochester Diabetic Neuropathy Study: reassessment of test and criteria for diagnosis and staged severity. Neurology 42: 1164–1170. England JD, Asbury AK (2004). Peripheral neuropathy. Lancet 363: 2151–2161. England JD, Gronseth GS, Franklin G et al. (2009a). Evaluation of distal symmetric polyneuropathy: the role
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of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve 39: 106–115. England JD, Gronseth GS, Franklin G et al. (2009b). Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Neurology 72: 177–184. England JD, Gronseth GS, Franklin G et al. (2009c). Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle Nerve 39: 116–125. England JD, Gronseth GS, Franklin G et al. (2009d). Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle Nerve 39: 116–125. England JD, Gronseth GS, Franklin G et al. (2009e). Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle Nerve 39: 116–125. Goranson LG, Mellegren SI, Lindal S et al. (2004). The effect of age and gender on epidermal nerve fiber density. Neurology 62: 774–777. Hughes RA (2002). Peripheral neuropathy. BMJ 324: 466–469. Hughes RA, Umapathi T, Gray IA et al. (2004). A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain 127: 1723–1730. Kahn SN, Bina M (1988). Sensitivity of immunofixation electrophoresis for detecting IgM paraproteins in serum. Clin Chem 34: 1633–1635. Kelly JJ, Karcher DS (2005). Lymphoma and peripheral neuropathy: a clinical review. Muscle Nerve 31: 301–313. Kelly JJ, Kyle RA, O’Brien PC et al. (1981). Prevalence of monoclonal proteins in peripheral neuropathy. Neurology 31: 1480–1483. Lucchinetti CF, Kimmel DW, Lennon VA (1998). Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 50: 652–657. Lupski JR, Garcia CA (2001). Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: CR Scriver, Al Beauder, WS Sly, D Valle (Eds.), The Metabolic and
Molecular Basis of Inherited Disease. 8th edn. New York, McGraw-Hill. pp. 5759–5788. Martyn CN, Hughes RA (1997). Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62: 310–318. McLeod JG, Tuck RR, Pollard JP et al. (1984). Chronic polyneuropathy of undetermined cause. J Neurol Neurosurg Psychiatry 47: 530–535. Novella SP, Inzucchi SE, Goldstein JM (2001). The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 24: 1229–1231. Rosenberg NR, Vermeulen M (2004). Chronic idiopathic axonal polyneuropathy revisited. J Neurol 251: 1128–1132. Said G (2001). Value of nerve biopsy. Lancet 357: 1220–1221. Saperstein DS, Wolfe GI, Gronseth GS et al. (2003). Challenges in the identification of cobalamin-deficient polyneuropathy. Arch Neurol 60: 1296–1301. Saporta ASD, Sottile SL, Miller LJ et al. (2011). Charcot Marie Tooth disease subtypes and genetic testing strategies. Ann Neurol 69: 22–23. Savage DG, Lindenbaum J, Stabler SP et al. (1994). Sensitivity of serum methymalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 96: 239–246. Sommer C, Lauria G (2007). Skin biopsy in the management of peripheral neuropathy. Lancet Neurol 6: 632–642. Stewart AG, Low PA, Fealey RD (1992). Distal small fiber neuropathy: results of test of sweating and autonomic cardiovascular reflexes. Muscle Nerve 15: 661–665. Sumner CJ, Sheth S, Griffin JW et al. (2003). The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60: 108–111. Tomkin GH (1973). Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. Br Med J 3: 673–675. Wise CA, Garcia CA, Davis SN et al. (1993). Molecular analyses of unrelated Charcot Marie Tooth (CMT) disease patients suggest a high frequency of the CMT1A duplication. Am J Hum Genet 53: 853–863.
Chapter 14
How to explore a patient with a chronic axonal polyneuropathy AMPARO GUTIERREZ AND JOHN D. ENGLAND* Department of Neurology, Louisiana State University Health Science Center, New Orleans, LA, USA
INTRODUCTION Peripheral neuropathies are common in neurological practice, and there are a variety of clinical presentations. The prevalence in the general population may be as high as 2.4% (Hughes, 2002). Through a combination of clinical findings, electrodiagnostic testing, and laboratory investigations tailored to the individual patients’ circumstances, most neuropathies can be categorized into their different subtypes, sensory being the most common followed by mixed types of neuropathy (both sensory and motor) and rarely pure motor. We will explore in this chapter how to evaluate a patient presenting with a chronic axonal polyneuropathy, which is one of the most common varieties of polyneuropathy seen.
EPIDEMIOLOGY The overall prevalence of polyneuropathy is about 2400 (2.4%) per 100 000, but it is much more prevalent in individuals older then 55 years of age, rising to 8000 (8%) per 100 000 (Martyn and Hughes, 1997). In the developed world the most common cause of peripheral neuropathy is diabetes mellitus. A community-based study estimated the prevalence of peripheral neuropathy in patients with type 2 diabetes mellitus to be 26.4% (Davies et al., 2006). In other parts of the world, such as Southeast Asia, India, and Africa, leprosy is still a major contributing cause of peripheral polyneuropathy.
DIAGNOSIS Although the clinical manifestations of a chronic neuropathy may vary widely, most can be categorized into a relatively limited number of possibilities on the basis of a
thorough history, focused neurological examination, and electrodiagnostic studies. The approach to the evaluation of the patient with a chronic axonal polyneuropathy should occur in a logical, evidence-based, and sequential manner. Historical features are indispensable for an accurate diagnosis. The physician should explore the presence of other medical conditions (including dietary supplements and vitamins), or exposure to toxins such as alcohol, heavy metals, and organic solvents. It is important to determine the rate of symptom progression, type of fibers involved, and pattern of symptoms. The most common clinical phenotype is that of slowly evolving distal sensory loss with varying degrees of muscle weakness, and occasionally autonomic symptoms. Symptoms are usually present for greater then 2 months and slowly worsen over time. The most common variety of polyneuropathy is a chronic distal symmetrical polyneuropathy (Rosenberg and Vermeulen, 2004). In this type of neuropathy nerves are involved in a “length- dependent” fashion; as such, symptoms usually begin in the toes/distal feet and spread centripetally. Sensory symptoms usually precede motor weakness. Myotatic reflexes are also affected in a length-dependent manner such that ankle reflexes are depressed or absent prior to the loss of other reflexes. The clinical picture is usually one of a stocking-glove sensory loss, distal wasting and weakness, and depressed or absent myotatic reflexes. This is an easily recognizable entity. Another form of neuropathy that is frequently encountered is a painful small fiber neuropathy. These patients commonly complain of burning pain, lancinating pain, burning dyesthesias, and sheet intolerance, but at the same time have a feeling of numbness. At onset the symptoms are infrequent or migratory in nature, and as time goes by the symptoms may become more persistent.
*Correspondence to: John D. England, M.D., The Grace Benson Professor and Head, Department of Neurology, LSUHSC School of Medicine, 1542 Tulane Avenue, Rm 721, New Orleans, LA 70112, USA. Tel: 504-568-4082, Fax: 504-568-7130, E-mail: jengla@ lsuhsc.edu
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The symptoms follow a distal to proximal distribution in most patients. On examination one mainly finds distal loss of pin prick, and temperature sensibility. These patients often present with complaints of chronic pain and the diffuse pain may be so severely disabling that it may limit a patient’s overall ability to function. Electrodiagnostic studies are sensitive, specific, and validated measures that are very useful in the assessment of peripheral neuropathy (Dyck et al., 1987). Utilizing electrodiagnostic studies one can determine whether the neuropathy is consistent with axonal loss or demyelination. Nerve conduction studies assess the shape, amplitude, latency, and velocity of most commonly affected nerves. Axonal loss leads to lower amplitudes and relatively preserved latencies and velocities. EMG can be useful in detecting active axonal damage, as evidenced by the presence of spontaneous muscle fiber activity at rest, as well as identifying signs of reinnervation damage in muscle. Electrodiagnostic studies are frequently normal in a painful neuropathy, where the small fibers are the ones mainly affected. In this type of neuropathy intraepidermal skin biopsy, as well as autonomic testing may serve as the most useful tools (England et al., 2009a).
ROLE OF LABORATORY TESTING Laboratory testing should start at potentially identifying the most common causes of axonal neuropathies and escalate in a determined fashion pending the obtained results. The majority of studies indicate that screening laboratory tests should initially consist of a complete blood count, erythrocyte sedimentation rate, a comprehensive metabolic panel (blood glucose, renal function, liver function), thyroid tests, serum B12, and serum protein electrophoresis. The above laboratory studies were identified as useful in current evidence-based practice guidelines (England et al., 2009b). The screening blood test with the highest yield is the blood glucose test, consistent with the well-known fact that diabetes mellitus is the most common cause of a distal symmetrical polyneuropathy. Several studies have highlighted the relatively high prevalence of prediabetes (impaired glucose tolerance) in patients who do not fulfill the criteria for definite diabetes mellitus (Novella et al., 2001). In these patients a glucose tolerance test, fasting blood glucose, or glycosylated hemoglobin should be considered as screening test for prediabetes. This test is particularly useful in screening patients with a small fiber painful neuropathy of unknown etiology. Vitamin B12 deficiency is frequently seen in patients with polyneuropathy. The yield of uncovering this deficiency is even greater when the metabolites of cobalamin (methylmalonic acid and homocysteine) are tested
(Saperstein et al., 2003). A large study demonstrated that measuring methylmalonic acid is more specific then homocysteine (Savage et al., 1994). Methylmalonic acid with or without homocysteine should also be checked when B12 is at the lower range of normal. Recent attention has been drawn to the complication of metformin use and B12 malabsorption, which occurs in 30% of diabetic subjects taking this medication (Tomkin, 1973). Monoclonal gammopathies are more common in patients with polyneuropathy than in the normal population. IgM monoclonal gammopathies may be associated with autoantibody activity, type I or II cryoglobulinemia, macroglobulinemia, or chronic lymphocytic leukemia. IgG or IgA monoclonal gammopathies may be associated with myeloma, POEMS syndrome, primary amyloidosis (Fig. 14.1), or chronic inflammatory conditions. One study of 279 consecutive patients with a polyneuropathy of unknown etiology found that 10% of these patients had a monoclonal gammopathy, a significant increase over that reported in community studies (Kelly et al., 1981). Serum protein immunofixation electrophoresis is more sensitive than serum protein electrophoresis, especially for detecting small or nonmalignant monoclonal gammopathies (Kahn and Bina, 1988). The yield of serum protein immunofixation electrophoresis is increased by 10% over routine SPEP for finding a monoclonal gammopathy. Therefore immunofixation is recommended. The history, clinical picture, and features of the electrodiagnostic studies found in the individual patient will determine if additional laboratory testing is necessary. An important aspect of the history in patients with a
Fig. 14.1. Sporadic familial amyloid polyneuropathy. Endoneurial deposit of amyloid in a sural nerve biopsy from a patient with a late onset, sporadic presentation of transthyretin-familial amyloid polyneuropathy. Note the predominant involvement of small myelinated fibers. 63. (From Plante-Bordeneuve et al. (2007). Diagnostic pitfalls in sporadic transthyretin-familial amyloid polyneuropathy (TTR-FAP). Neurology 69: 693–698.)
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY chronic axonal polyneuropathy is inquiry into the presence of other medical conditions, symptoms of systemic disease, recent viral or other infectious diseases, recent vaccinations, medications (including dietary supplements and vitamins), or exposure to toxins such as alcohol, heavy metals, or organic solvents (Tables 14.1 and 14.2). Laboratory testing should then be done to identify any underlying condition or possible etiology. If there is a suspicion of infection, inflammatory disease, or neoplasm, the cerebrospinal fluid should be analyzed as well. If, chronic heavy metal intoxication is suspected, analysis of the hair or nails should be done (England and Asbury, 2004).
ROLE OF GENETIC TESTING Hereditary neuropathies are an important subtype of polyneuropathy with a prevalence of 1:2500 people. They constitute a hereditary motor and sensory neuropathy and are the most common inherited disorder of the peripheral nervous system (Lupski and Garcia, 2001). A comprehensive family history should always be obtained in patients with a polyneuropathy. It is important to keep in mind that the hereditary neuropathies may exhibit phenotypic variability within families and that spontaneous genetic mutations do occur. The majority of genetically determined polyneuropathies are variants of Charcot Marie Tooth (CMT) disease. The two common causes of a hereditary demyelinating polyneuropathy are CMT1A, where patients exhibit a duplication of the PMP22 gene and CMTX (Wise et al., 1993). Axonal forms of CMT, Type 2, are most commonly caused by MFN2 mutations, these account for 20 21% of Type 2 cases (Saporta et al., 2011). An X-linked form of CMT, CMTX, is caused by mutations in connexin 32. Interestingly, this mutation may manifest as either an axonal or demyelinating neuropathy (Bort et al., 1997). CMTX is the most common type of “axonal” hereditary neuropathy. The high cost of genetic testing necessitates a logical stepwise approach to testing (Fig. 14.2).
ROLE OF CLINICAL AUTONOMIC TESTING Autonomic nervous system dysfunction may be part of a chronic axonal polyneuropathy. In distal axonal symmetrical polyneuropathies with autonomic involvement, the most common clinical findings are abnormalities of sweating and circulatory instability in the feet (England et al., 2009e). Various types of autonomic testing exist and provide indices of cardiovagal, adrenergic, and postganglionic sudomotor function. Heart rate variability is a simple and reliable test of cardiovagal function. It can detect
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the presence of diabetic polyneuropathy with nearly the same sensitivity as nerve conduction studies (Dyck et al., 1992). The quantitative sudomotor axon reflex test (QSART) may be used and can detect distal sudomotor loss with a sensitivity of 75 90% (England et al., 2009c). Analysis of available studies on autonomic testing indicate that a combination of autonomic reflex screening tests provide distinct advantages over just using a single modality (Stewart et al., 1992). The composite autonomic scoring scale (CASS), which includes QSART, orthostatic blood pressure, heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat BP measurement to Phases II and IV of the Valsalva manuver, tilt and deep breathing provides the highest sensitivity and specificity for documentation of autonomic dysfunction (England et al., 2009d).
ROLE OF NERVE BIOPSY There is little indication for a nerve biopsy in the usual cases of chronic distal symmetrical axonal polyneuropathy. Nerve biopsy should be considered when the diagnosis remains uncertain after laboratory and electrodiagnostic testing have been done, or when confirmation of the diagnosis is needed before initiating aggressive therapies. Nerve biopsy can be extremely valuable in cases of suspected vasculitic (Fig. 14.3), inflammatory, infectious, or neoplastic diseases, which can rarely present as a symmetrical polyneuropathy (Said, 2001).
ROLE OF SKIN BIOPSY Epidermal skin biopsy can be performed in patients with burning, numbness, and pain in whom the nerve conductions are usually normal. These patients may have involvement of the small, somatic, unmyelinated intraepidermal nerve fibers which can be quantified by the skin biopsy. The skin biopsy can also assess the autonomic fibers innervating sweat glands (Sommer and Lauria, 2007). Skin biopsy is a technique that involves a 3 mm punch biopsy of skin taken from standardized sites on the leg. The tissue is immunostained with antiprotein-gene-product (PGP) 9.5 antibodies. Both bright-field immunohistochemistry and indirect immunofluorescence have provided standard values of intraepidermal nerve fiber density (Chien et al., 2001). Staining with PGP 9.5 allows for identification and counting of intraepidermal nerve fibers (IENF). This technique has been validated as a reliable method for IENF density determination with good intra- and interobserver reliability in normal controls and patients with a distal symmetrical polyneuropathy (Goranson et al., 2004). In particular, patients who are suspected of having a predominately small fiber length-dependent
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Table 14.1 Different etiologies of axonal polyneuropathies Diseases: Diabetes mellitus Renal insufficiency Liver disease Porphyria Malabsorption (inflammatory bowel and short bowel) Celiac disease Primary systemic amyloidosis Leprosy Lyme HIV infection Carcinoma Lymphoma IgG, IgA Cryglobulinemia Multiple myeloma Drugs: Amiodarone Chloramphenicol Chloroquine Colchicine Dichloroacetate Disulfiram Hydralazine Interferon-a Isoniazid Leflunomide Metronidazole Misonidazole Nitrofurantoin Nucleosides (antiretrovirals) Phenytoin Taxol Thalidomide Vinca alkaloids Toxins: Acrylamide monomer Arsenic Alcohol Carbon disulfide Ethylene oxide Hexacarbons Methyl bromide Mercury Organophosphates Thallium
Symptoms S, SM rarely M SM S or SM M or SM S or SM
Comments Most common Controlled with dialysis Mild Rare Deficiency of vitamins E or B12, some basis unknown
S or SM SM, may have small fiber component S, SM S>M S>M SM SM SM SM S, M, or SM
May have autoimmune basis Most have serum paraprotein, small fiber with autonomic symptoms Involves cutaneous nerves in cold parts of the body Focal or multifocal radiculopathy or neuropathy, facial neuropathy common Mainly lung cancer, positive antibodies (Anti-Hu, Anti-CV2 and Anti-Ri)
Chronic hepatitis C Uncommon
SM SM SM S or SM SM SM S>M S, SM SM S, SM S or SM S or SM SM S>M S>M S>M S>M S>M
Dose related Rare Principle toxicity is myopathy Principle toxicity is myopathy Delayed onset After months to years of exposure Pyridoxine antagonist Reversible, uncommon Pyridoxine antagonist Panmodal Mainly large fiber Dose-related toxicity Rapidly progressive Painful, limits dose exposure Doses > 200 mg/day Doses > 200 mg/m2 Insensitivity to pain and touch Onset in hands > feet, autonomic neuropathy
S>M
Large fiber neuropathy, can mimic Guillain Barre Syndrome (GBS); cause encephalopathy with large doses Painful sensory symptoms, prominent systemic effects Panmodal sensory loss Sensory symptoms followed by motor Inhalational exposure Inhalational abuse Loss of color vision early Predominately motor, usually with tremor Delayed neuropathy after exposure, myelopathy can be seen Painful sensory neuropathy, alopecia, systemic effects
SM S, SM S>M SM SM M>S M>S M>S S>M
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY
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Table 14.2 Purely sensory types Diseases: Vitamin B12 Acromegaly Chronic obstructive pulmonary disease Carcinoma
S S S S
Connective tissue disease: systemic lupus, rheumatoid arthritis, systemic sclerosis, Sjogren’s Drugs: Almitrine Bortezomib Ethambutol Etoposide(VP-16) Nitrous oxide
May be associated with myelopathy Carpal tunnel frequent Only in severe cases Paraneoplastic ganglionitis with small cell or breast cancer, positive antibodies (Anti-Hu, Yo, Ri, Tr, MA, and CV2) Systemic manifestations
S
S S S S S
Platinum drugs: cisplatin carboplatin oxaliplatin
S
Pyridoxine
S
Panmodal sensory loss, reversible Painful, most recover after drug is stopped Mild, reversible Not frequent Inhalational abuse, presents with ataxia, megaloblastic anemia (worsen in presence of B12 deficiency) Severe large fiber, dose related Distal large fiber, associated with hypomagnesemia Less common but also distal large fiber Acute neurosensory syndrome with dysesthesias and cold-induced pharyngolaryngeal dysesthesias, and late cumulative distal large fiber (>540 mg/m2) Doses > 200 mg/day
S-sensory, M-motor
Evaluation of suspected hereditary neuropathies Positive Family History
Negative Family History
EMG/NCS
EMG/NCS
Demyelinating
Index of suspicion for CMT high
Axonal 30% of mutations are de novo, molecular testing
AR
AD
GJB1 12%
MFN2 mut 21%
AR
Second tier
PMP22 dup 70%
X
MPZ mut 5% PMP22 mut 2.5%
MPZ mut 5%
Third tier
First tier
AD
EGR2 mut LITAF mut
RAB7 mut GDAP1 mut GARS mut NEFL mut HSPB1 mut
PRX mut GDAP1 mut
X GJB1 12%
Demyelinating
Axonal
PMP22 dup GJB1 mut
MFN2 mut GJB1 mut
MPZ mut 5% PMP22 mut 2.5%
MPZ mut 5%
EGR2 mut LITAF mut PRX mut GDAP1 mut
RAB7 mut GARS mut NEFL mut HSPB1 mut GDAP1 mut
Fig. 14.2. Decision algorithm for use in the diagnosis of suspected hereditary polyneuropathies using family history and NCSs. PMP22, peripheral myelin protein 22; MPZ, myelin protein zero; PRX, periaxin; GDAP1, ganglioside-induced differentiationassociated protein 1; GJB1, gap-junction beta-1 protein (connexin 32); MFN2, mitofusin 2; EGR2, early growth response 2; LITAF, lipopolysaccharide-induced tumor necrosis factor a; RAB7, small guanosine triphosphate late endosomal protein; GARS, glycyl-transfer RNA synthetase; NEFL, neurofilament light chain; HSPB1, heat shock protein beta-1. (Reprinted and modified with permission from England et al., 2009c.)
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Fig. 14.3. Necrotizing arteritis in a muscle biopsy specimen. Paraffin embedded section of a muscle biopsy specimen from a patient with mononeuritis multiplex, to show fibrinoid necrosis and transmural cellular infiltration. H & E. Original magnification: 25.
sensory polyneuropathy may benefit from skin biopsy with IENF analysis since this test will demonstrate the reduction in the density of intraepidermal nerve fibers typically found in the distal rather than proximal leg, thereby helping to confirm the diagnosis (Fig. 14.4).
ETIOLOGIES OF CHRONIC POLYNEUROPATHIES Painful small fiber neuropathies
Fig. 14.4. (A) Normal epidermal fiber density. (B) Abnormal epidermal fiber density. (By permission of Therapath.)
Painful small fiber neuropathies are more likely associated with diabetes, prediabetes, sporadic amyloidosis, HIV infection, and alcohol abuse. Tangier and Fabry diseases, two inherited disorders, may also rarely present with a small fiber painful neuropathy. Hyperlipidemia has recently been recognized as a potential risk factor for a small fiber neuropathy (Hughes et al., 2004). Neuropathic pain is frequently reported in patients with sarcoidosis, a multisystemic inflammatory disorder characterized by the presence of granulomas (Fig. 14.5). One study reported that 30% of patients with sarcoid complained of burning feet and one third of them had a small fiber neuropathy (Bakkers et al., 2009). Many cases of painful “small fiber” neuropathy remain crytogenic even after a thorough workup.
Chronic sensory or sensory motor neuropathies This form of neuropathy constitutes the largest diagnostic group. There are many etiologies of this neuropathy including systemic causes, metabolic abnormalities, nutritional deficiencies, and exogenous toxins (Tables 14.1 and
Fig. 14.5. Epineural sarcoid granuloma–superficial peroneal nerve biopsy specimen from a patient with multifocal neuropathy. The neighboring nerve fascicles look normal at this level. 1 mm thick plastic section. Thionin blue. Original magnification: 40.
HOW TO EXPLORE A PATIENT WITH A CHRONIC AXONAL POLYNEUROPATHY 14.2). The most prevalent etiology in the developed world is diabetes and prediabetes (Dyck and Thomas, 1999; Novella et al., 2001; Sumner et al., 2003). Less frequently a chronic axonal polyneuropathy may be immune mediated. The associated monoclonal proteins are mostly IgM or IgG; in some cases there is binding to sulfatide. Even less frequently there may be a polyneuropathy associated with IgA monoclonal gammopathy. Clinically overt peripheral nervous system (PNS) involvement is common in patients with cancer, occurring in 1.7 16% of cases (Croft and Wilkinson, 1965). Chemotherapy and radiotherapy are the most common causes of PNS disorders in patients with cancer. The combination of several neurotoxic products, especially in the case of cancer recurrence, or the association of neurotoxic chemotherapy and radiotherapy, increases the risk of toxic side-effects, which explains some severe neuropathies (Antoine and Camdessanche, 2007) (Fig. 14.6). Malignancies are sometimes associated with production of specific autoantibodies which may be associated with chronic axonal neuropathies. Neuropathies associated with anti-Hu antibodies (also known as ANNA-1) are the most frequent and consist mainly of a subacute sensory neuronopathy (Lucchinetti et al., 1998). Less frequent are neuropathies associated with anti-CV2 (anti-CRMP5) which are usually sensorimotor axonal neuropathies. The most frequently associated cancer is small cell carcinoma (Amato and Collins, 1998). Malignant, in particular leukemic and lymphamatous, cells can occasionally infiltrate peripheral nerves leading to a polyneuropathy (Kelly and Karcher,
Fig. 14.6. Malignant infiltrate in peripheral nerves. Malignant infiltration in a superficial radial nerve biopsy specimen from a patient with a subacute progressive multifocal polyneuropathy and monoclonal gammopathy. Note the presence of malignant cells in the subperineurial and in the epineurial areas. 1 mm thick plastic section. Thionine blue. Original magnification: 63.
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2005). Rarely, a peripheral neuropathy can be seen in non-Hodgkin lymphomas and Hodgkin disease (Briani et al., 2011).
CONCLUSION The cause of most polyneuropathies is evident when the information obtained from the medical history, neurological examination, and electrodiagnostic studies are combined with simple screening laboratory tests. A comprehensive investigation yields an etiological diagnosis in a substantial number of neuropathies, although in 10 15% of patients with a chronic polyneuropathy a cause cannot be found; this idiopathic neuropathy presents more often in middle or old age (McLeod et al., 1984).
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